XRN2 Links Transcription Termination to DNA Damage and Replication Stress

Julio C. Morales, Patricia Richard, Praveen L. Patidar, Edward A. Motea, Tuyen T. Dang, James L. Manley, David A. Boothman

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

XRN2 is a 5’-3’ exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents. We demonstrate that the DSBs that arise with XRN2 loss occur at transcriptional pause sites. XRN2-deficient cells also exhibited an R-loop- and transcription-dependent delay in DSB repair after ionizing radiation, suggesting a novel role for XRN2 in R-loop resolution, suppression of replication stress, and maintenance of genomic stability. Our study highlights the importance of regulating transcription-related activities as a critical component in maintaining genetic stability.

Original languageEnglish (US)
Article numbere1006107
JournalPLoS Genetics
Volume12
Issue number7
DOIs
StatePublished - Jul 1 2016

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Genomic Instability
DNA replication
DNA Replication
DNA damage
DNA Damage
transcription (genetics)
DNA
damage
Double-Stranded DNA Breaks
Ionizing Radiation
genomics
Hypersensitivity
exoribonucleases
Maintenance
genetic stability
ionizing radiation
hypersensitivity
repair
cells
5'-exoribonuclease

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Morales, J. C., Richard, P., Patidar, P. L., Motea, E. A., Dang, T. T., Manley, J. L., & Boothman, D. A. (2016). XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS Genetics, 12(7), [e1006107]. https://doi.org/10.1371/journal.pgen.1006107

XRN2 Links Transcription Termination to DNA Damage and Replication Stress. / Morales, Julio C.; Richard, Patricia; Patidar, Praveen L.; Motea, Edward A.; Dang, Tuyen T.; Manley, James L.; Boothman, David A.

In: PLoS Genetics, Vol. 12, No. 7, e1006107, 01.07.2016.

Research output: Contribution to journalArticle

Morales, JC, Richard, P, Patidar, PL, Motea, EA, Dang, TT, Manley, JL & Boothman, DA 2016, 'XRN2 Links Transcription Termination to DNA Damage and Replication Stress', PLoS Genetics, vol. 12, no. 7, e1006107. https://doi.org/10.1371/journal.pgen.1006107
Morales JC, Richard P, Patidar PL, Motea EA, Dang TT, Manley JL et al. XRN2 Links Transcription Termination to DNA Damage and Replication Stress. PLoS Genetics. 2016 Jul 1;12(7). e1006107. https://doi.org/10.1371/journal.pgen.1006107
Morales, Julio C. ; Richard, Patricia ; Patidar, Praveen L. ; Motea, Edward A. ; Dang, Tuyen T. ; Manley, James L. ; Boothman, David A. / XRN2 Links Transcription Termination to DNA Damage and Replication Stress. In: PLoS Genetics. 2016 ; Vol. 12, No. 7.
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